The precise mechanisms of the neuropathogenesis of HIV-1 infection are unknown. We examined the interaction between HIV-1 and rat cerebellar cells (RCC) to determine whether the virus may be directly cytopathic to neural cells. Primary cultures of RCC were derived from 8-day-old rat cerebella and grown in a chemically defined medium in presence or absence of cytosine arabinoside (AraC, 10 micro-M). Two HIV-1 isolates (HIV-1,br and NA-4) were from AIDS patients with, and the other two (HIV-1,bru or LAV and HIV-1,451) were from patients without overt neurological symptoms. RCC were exposed for 24 h to equal virus inocula 24 h after seeding. Cell type-specific markers were assayed at indicated times post exposure. RCC cultures consisted of neurons, astrocytes, microglia, and oligodendrocytes (in order of decreasing abundance). All cell types except neurons proliferated in absence of AraC. Upon exposure to HIV-1, progressive disruption of neural network and destruction of cells were observed. The cytopathic effect increased with time and virus dose. HIV-1 specific DNA and RNA were detected by polymerase chain reaction (PCR) using multiple primers and Northern blotting, respectively. Culture supernatants occasionally contained viral proteins. HIV-1,br and NA-4 were consistently more cytopathic and infectious than HIV-1,bru and HIV-1,451. These results demonstrate that HIV-1 is cytopathic to non-dividing rat brain cells in culture, and that HIV-L,br from the brain of an AIDS dementia patient (Anand, R. et al., Virology 1989; 168:79-89) is more potent than other isolates tested. These results suggest that HIV-1 may exert a direct neurocytopathic effect in adult brain. Currently, we are characterizing the nature of the HIV-1,br associated neurocytopathic effect and confirming the infectivity. It is important to define the cell surface molecules (receptors) on neurons that interact with HIV-1, especially with isolates such as HIV-l,br.